A Concise and Cascade Synthesis of Batracylin and Substituted Isoindolo-[1,2-b]quinazolin-12(10H)-ones

Abstract

A concise, highly convergent, and practical synthesis of the clinical-phase anticancer agent batracylin in a two-stage process in excellent yield is described. The B and C rings of this tetracyclic heterocycle are constructed by cascade cyclization of 5-nitro-2-aminobenzyl alcohol with 2-cyanomethyl benzoate in trifluoroacetic acid in good yield in a single-pot reaction. A plausible mechanism for the cascade reaction is also proposed. As part of these studies, a range of batracylin derivatives with different substituents on the C and D rings are synthesized.

batracylin - antineoplastic agents - cascade cyclization - 5-nitro-2-aminobenzyl alcohol

References and Notes

1 Kabbe HJ. Justus Liebigs Ann. Chem.  1978,  398 

2a Plowman J. Paul KD. Atassi G. Harrison SD. Dykes DJ. Kabbe HJ. Narayanan VL. Yoder OC. Invest. New Drugs  1988,  6:  147 

2b Dzierzbicka K. Trzonkowski P. Sewerynek PL. Mysliwski A. J. Med. Chem.  2003,  46:  978 

2c Guillaumel J. Léonce S. Pierre A. Renard P. Pfeiffer B. Arimondo PB. Monneret C. Eur. J. Med. Chem.  2006,  379 

2d Yilin R. Yun Feng C. Ting C. Chen AY. Yu C. Liu LF. Cheng CC. Pharm. Res.  1993,  10:  918 

3 Waud WR. Hamson SD. Gilbert KS. Laster WR. Griswold DP. Cancer Chemother. Pharmacol.  1991,  27:  456 

4 Mucci-LoRusso P. Polin L. Bissery MA. Valeriote F. Plowman J. Luk GD. Corbett TH. Invest. New Drugs  1989,  7:  295 

5a Amin AH. Mehta DR. Samarth SS. Prog. Drug Res.  1970,  14:  218 

5b Gupta OP. Anand KK. Ghattak Ray BJ. Atal CK. Indian J. Exp. Biol.  1978,  16:  1075 

6a Mitscher LA. Wong W.-C. DeMeulenaere T. SulkoT . Drake S. Heterocycle  1981,  15:  1017 

6b Mitscher LA. Baker W. Med. Res. Rev.  1998,  18:  363 

7a Ma ZZ. Hano Y. Nomura T. Chen YJ. Heterocycles  1997,  46:  541 

7b Ma ZZ. Hano Y. Nomura T. Chen YJ. Heterocycles  1999,  51:  1883 

8 Ames MM. Mathiesen D. J. Chromatogr.  1989,  491:  488 

9a Meegalla SK. Stevens GJ. McQueen CA. Chen AY. Yu C. Liu LF. Barrows LR. LaVoie EJ.
J. Med. Chem.  1994,  37:  3434 

9b Rosevear J. Wilshire JFK. Aust. J. Chem.  1990,  43:  339 

9c Martínez-Viturro CM. Domínguez D. Tetrahedron Lett.  2007,  48:  1023 

10a Servais A. Azzouz M. Lopes D. Courillon C. Malacria M. Angew. Chem. Int. Ed.  2007,  46:  576 

10b Beaume A. Courillon C. Derat E. Malacria M. Chem. Eur. J.  2008,  16:  1228 

11 Comins DL. Schilling S. Zhang Y. Org. Lett.  2005,  7:  95 

12

A solution of methyl 2-cyanobenzoate (0.5 g, 0.003 mol), 2-aminophenylmethanol (0.57 g, 0.0047 mol) in TFA (10 mL) was refluxed for 10-12 h, and the progress of the reaction was monitored by TLC. After complete disappearance of the starting material, the reaction was quenched with ice water and the aqueous layer extracted with CH₂Cl₂ (2 × 10 mL). The combined extracts washed with aq NaHCO₃ (10%, 25 mL) dried over anhyd Na₂SO₄, filtered, and concentrated under vacuum. The crude product was then purified by column chromatography using CH₂Cl₂ as an eluent; yield 0.43 g (62%).

13

Isoindolo [1,2- b ]Quinazolin-12(10 H )-one (12)
Yield 62%; mp 186 ˚C (lit. 175-177 ˚C);⁸ IR (KBr): 1724, 1650 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 7.6 Hz, 1 H, ArH), 7.90 (d, J = 6.7 Hz, 1 H, ArH), 7.74-7.63 (m, 2 H, ArH), 7.51 (d, J = 8.0 Hz, 1 H, ArH), 7.34-7.18 (m, 3 H, ArH), 5.00 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.2, 148.7, 140.0, 134.0, 133.2, 132.4, 130.1, 128.4, 127.4, 127.3, 127.2, 122.8, 121.9, 121.2, 40.2 ppm. MS: m/z (%) = 235.2 [M + H]⁺. Anal. Calcd for C₁₅H₁₀N₂O (234.2): C, 76.91; H, 4.30; N, 11.96; O, 6.83. Found: C, 76.83; H, 4.25, N, 4.26, O, 6.70.

14

8-Bromoisoindolo[1,2- b ]quinazolin-12(10 H )-one (24)
Yield 63%; mp 214 ˚C. IR (KBr): 1731, 1645 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.02 (d, J = 7 Hz, 1 H, ArH), 7.90 (d, J = 7 Hz, 1 H, ArH), 7.84-7.77 (m, 2 H, ArH), 7.57 (s, 1 H, ArH), 7.51 (dd, J = 8.2, 1.5 Hz, 1 H, ArH), 7.34 (d, J = 8.5 Hz, 1 H, ArH), 4.93 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 165.9, 149.2, 139.3, 133.7, 133.1, 132.4, 131.1, 129.8, 128.8, 124.4, 122.7, 121.9, 119.5, 40.7 ppm. MS: m/z (%) = 313.1 [M + H]⁺. Anal. Calcd for C₁₅H₉BrN₂O (311.99): C, 57.53; H, 2.90; N, 8.95; O, 5.11. Found: C, 57.48; H, 2.85; N, 8.85; O, 5.1. 7-Fluoroisoindolo[1,2- b ]quinazolin-12(10 H )-one (25) Yield 57%; mp 213 ˚C. IR (KBr): 1729, 1646 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.06 (d, J = 7.2 Hz, 1 H, ArH), 7.92 (d, J = 6.8 Hz, 1 H, ArH), 7.75-7.69 (m, 2 H, ArH), 7.22 (dd, J = 2.4, 9.6 Hz, 1 H, ArH), 7.19-7.12 (m, 1 H, ArH), 6.98-6.93 (m, 1 H, ArH), 4.95 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 149.9, 142.1, 133.0, 132.6, 132.3, 131.6, 131.1, 130.4, 127.8, 127.7, 123.5, 123.2, 122.3, 40.3 ppm. MS: m/z (%) = 253.2 [M + H]⁺. Anal. Calcd for C₁₅H₉FN₂O (252.07): C, 71.42; H, 3.60; N, 11.11; O, 6.34. Found: C, 71.34; H, 3.50; N, 11.01; O, 6.29. 9-Methylisoindolo[1,2- b ]quinazolin-12(10 H )-one (26) Yield 54% mp 243 ˚C. IR (KBr): 1721, 1650 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.04 (d, J = 6.8 Hz, 1 H, ArH), 7.92-7.78 (m, 3 H, ArH), 7.26-7.24 (m, 2 H, ArH), 7.14-7.10 (m, 1 H, ArH), 4.85 (s, 2 H, CH₂), 2.49 (s, 3 H, CH₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 148.4, 139.8, 135.4, 134.1, 132.8, 132.0, 130.4, 129.3, 128.3, 125.7, 123.1, 122.3, 119.8, 39.4, 18.1 ppm. MS: m/z (%) = 249.2 [M + H]⁺. Anal. Calcd for C₁₆H₁₂N₂O (248.09): C, 77.40; H, 4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.78; N, 11.19; O, 6.35.
7,8-Difluoroisoindolo[1,2- b ]quinazolin-12(10 H )-one (27) Yield 53%; mp 278 ˚C. IR (KBr): 1729, 1647 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.04 (d, J = 7.6 Hz, 1 H, ArH), 7.9 (d, J = 6.8 Hz, 1 H, ArH), 7.75-7.68 (m, 2 H, ArH), 7.34 (m, 1 H, ArH), 7.00 (t, 8.8 Hz, 1 H, ArH), 4.90 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 180.0, 158.5, 141.2, 133.2, 132.5, 130.3, 123.4, 122.4, 116.9, 115.4, 110.0, 40.3 ppm. MS: m/z (%) = 271.2 [M + H]⁺. Anal. Calcd for C₁₅H₈F₂N₂O (270.06): C, 66.67; H, 2.98; N, 10.37; O, 5.92. Found: C, 66.58; H, 2.87; N, 10.29; O, 5.83.
10-Phenylisoindolo[1,2- b ]quinazolin-12(10 H )-one (28) Yield 72%; mp 210 ˚C. IR (KBr): 1732, 1646 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.10 (d, J = 7.5 Hz, 1 H, ArH), 7.88-7.78 (m, 3 H, ArH), 7.49 (d, J = 7.0 Hz, 1 H, ArH), 7.35-7.21 (m, 8 H, ArH), 6.47 (s, 1 H, CH) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 174.8, 165.9, 153.2, 143.1, 138.9, 133.9, 133.8, 132.8, 129.7, 128.8, 128.7, 128.1, 127.8, 127.8, 127.3, 126.4, 126.2, 123.2, 122.3, 54.5 ppm. MS: m/z (%) = 311.2 [M + H]⁺. Anal. Calcd for C₂₁H₁₄N₂O (310.11): C, 81.27; H, 4.55; N, 9.03; O, 5.16. Found: C, 81.20; H, 4.50; N, 8.92; O, 5.10.
10-Methylisoindolo[1,2- b ]quinazolin-12(10 H )-one (29) Yield 70%; mp 123 ˚C. IR (KBr): 2925, 1728, 1648 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 7.6 Hz, 1 H, ArH), 7.81 (d, J = 7.2 Hz, 1 H, ArH), 7.64-7.57 (m, 2 H, ArH), 7.40 (d, J = 8.0 Hz, 1 H, ArH), 7.26-7.21 (m, 1 H, ArH), 7.18-7.15 (m, 1 H, ArH), 7.12 (d, J = 6.8 Hz, 1 H, ArH), 5.41 (q, J = 6.4 Hz, 1 H, CH), 1.51 (d, J = 6.4 Hz, 3 H, CH₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 167.0, 149.9, 139.8, 134.5, 132.9, 132.0, 130.6, 128.6, 127.8, 127.7, 127.7, 127.5, 123.2, 122.1, 47.9, 23.6 ppm. MS: m/z (%) = 249.2 [M + H]⁺. Anal. Calcd for C₁₆H₁₂N₂O (248.09): C, 77.40; H, 4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.81; N, 11.20; O, 6.36.

15 Kato T, Kawamura K, Morita M, and Uchida C. inventors; WO  2005/049608 A1. 

16 Eguchi S. Goto S. Heterocycl. Commun.  1999,  1:  1 

17

8-Aminoisoindolo[1,2- b ]quinazolin-12(10 H )-one (1) Mp 280-282 ˚C (recrystallized from CH₂Cl₂). IR (KBr): 3474, 1688, 1645 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.95 (d, J = 8.0 Hz, 1 H, ArH), 7.86 (d, J = 6.8 Hz, 1 H, ArH), 7.78-7.68 (m, 2 H, ArH), 7.13 (d, J = 8.4 Hz, 1 H, ArH), 6.52 (dd, J = 2.4, 8.2 Hz, 1 H, ArH), 6.46 (s, 1 H, ArH), 5.54 (s, 2 H, NH₂), 4.80 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.9, 148.8, 143.8, 134.2, 132.8, 131.3, 129.7, 129.4, 128.8, 122.8, 122.6, 121.2, 113.2, 111.7, 40.3 ppm. MS: m/z (%) = 250.2 [M + H]⁺. Anal. Calcd for C₁₅H₁₁N₃O (249.09): C, 72.28; H, 4.45; N, 16.86; O, 6.42. Found: C, 72.19; H, 4.38; N, 16.80; O, 6.35.